Hemophilia A, Factor VIII, and the Future

Hemophilia has been studied tremendously. Before treatment was available for this disorder, most boys perished before reaching 20 years of age. This was often due to uncontrolled bleeding. We can attempt to understand hemophilia through Factor VIII, a coagulation protein factor that is missing in those that have the hemophilia A disorder. Without this factor, and without the benefit of gene therapy to treat this disorder, patients have continued to suffer as scientists pursue a viable solution to this malady.

There are several topics that are important in this field of study. First of all, the effect of route of administration of human recombinant Factor VIII on its immunogenicity in Hemophilia A mice is significant because it shows the effects of recombinant Factor VIII, in terms of its immunogenicity, in Hemophilia A mice requires further research and is, as of yet, unclear. This shows vast significance in that at this point the effect of route of administration of Factor VIII on Hemophilia A mice is not completely understood and could be pursued to further establish a proven method for human recombinant Factor VIII application. This would help evolve the way factor VIII is produced and eventually lead to gene therapy improvements in the treatment of hemophilia A.

Another topic that is significant in this field of study is how recombinant Factor VIII is currently used along with its future plans for use. An article points out that there are opportunities for further advances in the concerns for safety of new treatments and costs could be perhaps reduced, as currently the resources required for replacement therapy remain extraordinarily expensive to remain effective. Another article points out that "The issue of availability and, in particular, of costs of clotting factor concentrates remains the main barrier to the diffusion of prophylaxis, since these costs are prohibitive particularly for developing countries."[2]

With testing on mice showing little success, and citations of costs being expensive for some countries, another significant factor is the treatment of hemophilia A patients at this current time.

Treatment of a hemophilia A patient with a Factor VIII inhibitor is extremely significant. Inhibitor eradication allows Factor VIII to remain effective and active. Understanding this will contribute to the future of Factor VIII development in regards to hemophilia A patients, who could expect, ideally that the effectiveness of such treatments would improve and also spend fewer resources, in the future. With the testing on mice eventually reaching a successful point, hemophilia A recovery could expect to lower its cost and become more widely available to hemophilia A patients around the world.

Historically, the significance of one perspective is not always obvious unless coupled with the insights from other sources, examples, and articles. Hemophilia was named in 1828 as a derivative of the term "haemorrhaphilia". Hemophilia in the 21^st century is not uniform in its operation, as indicated by a review on hemophilia from Singapore. Historically, and geographically, hemophilia has its own form and has also been documented as far back as the 2^nd century in Talmudic writings. "The first written account of haemophilia occurred in the second century in the Babylonian Talmud. In it RabbiJudah haNasi, redactor of the Mishneh, wrote: "If she circumcised her first child and he died, and a second one also died, she must not circumcise her third child." This passage refers to both the prolonged bleeding caused by circumcision and to the maternal inheritance of the disease."[6]

The way we see hemophilia now can be dated back to the 1940s. It was then that we had reached our current understanding of hemophilia as a deficiency of clotting factors. In 1960, according to another article, "the average life expectancy for severe hemophilia A was less than 20 years, and the quality of life was generally devastating from joint bleeding complications or intracranial hemorrhage."[5]

1970 introduced the hemophilia treatment centers and home treatment programs. Plasma-derived factor products became widely available, and the death rate for patients with hemophilia A showed a great deal of improvement by the late 1970s. The significance in the improvement within each decade is quite notable. "With vigorous medical support primarily through hemophilia treatment centers and home treatment programs, and with plasma-derived factor VIII products widely available, the death rate for hemophilia A had improved dramatically by the late 1970s."[5]

In the early 1980s, the epidemic of HIV infected nearly 75% of the severe hemophilia A patients. The source of the HIV infection, the plasma-derived factor VIII products, was thought to be life saving but proved otherwise. A second epidemic consisting of hepatitis C also spread through the plasma-derived factor VIII products. Hepatitis C, being unidentified until 1989, developed within the community of hemophilia A patients until the late 1990s.

Over the last 20 years, there have been 4 independent developments that improved the clinical situation of hemophilia A patients. The first was the introduction of effective treatments for HIV infection. The second includes treatments that provide cure for a significant portion of individuals that have hepatitis C. The third development is that the preparation of plasma-derived products have been improved to the point where no transmission of HIV, hepatitis C, or other virus have been documented with these modern plasma-derived factor VIII preparations since 1990.

"The fourth major development for hemophilia A over the past 20 years has been the provision of recombinant factor VIII, widely available shortly after completion of the clinical trials in

Recombinant factor VIII has a strong safety record, allowing for the normal life expectancy for hemophilia A patients.

These 4 developments have turned the tide in the battle against hemophilia A. With the inclusion of these new developments, hemophilia A patients now have a higher hope for living, as well as cutting out the possibility of incurring new disease. That is a vast improvement from over half a century ago. To understand how much has improved, we need to understand the modern problem of factor VIII inhibition.

Factor VIII inhibition revolves around the factor VIII, which is responsible for blood clotting, the artificial factor VIII, which is used to support blood clotting in patients that are missing the natural factor VIII, and also the level of inhibition by alloantibodies. Simply put, with factor VIII inhibition, blood clotting will not be able to occur. Suggesting the use of agents that bypass factor VIII activity has been realized, and this leads the way towards better understanding patient-specific and treatment-related factors that will show how anti-factor VIII antibody production works, and how to avoid this inhibition within the body, and allow for normal blood coagulation.

Several alternatives to factor VIII infusion into hemophilia A patients have been recombinant factor VIIa, porcine factor VIII, and high-dose human factor VIII. Even then, all of these alternatives are a temporary solution to a problem that could, ultimately, be corrected through gene therapy. We look at these current issues through the ideas of viable mouse testing, costs, and eventual succession on to gene therapy. Will these alternatives be able to show us through testing on mice how effective they are? What are the costs for each type of treatment, and how can we improve this? Will these treatments be rendered obsolete by gene therapy when it eventually becomes a viable option for hemophilia A patients?

There are four aspects that we will look in depth at. These are linked to the main theme of hemophilia treatment methods and their continued usefulness. These are the effect of human recombinant Factor VIII in hemophilia A mice, the effect of prophylaxis on hemophiliac children, hemophilia in developing countries, including Singapore, and the future of recombinant factor VIII.

The first article shows lukewarm results: "Product related factors of protein therapeutics contribute to its immunogenic response. The route of administration of the protein plays an important role in the elucidation of antibody response against administered protein (6, 12). The effect of such product related factors on antibody development against Factor VIII was evaluated in Hemophilia A mice."[1]

Unfortunately, not every experiment produces clear-cut results, and in this case, the results within the separate groups tested within this experiment could not be established as having statistical significance. As cited within the article, "Further investigations that could shed light on the mechanism of inhibitor development are certainly necessary."[1]

The second aspect of factor VIII that I would like to discuss includes primary prophylaxis in children with hemophilia, which contains an open issue and perspective:

"Despite the general lack of high-level evidence supporting clinical choices for the optimal prophylactic regimen, convincing findings from observational studies show that the early start of prophylaxis may be individualized on the basis of the bleeding pattern. This led to tailored doses and/or frequencies of prophylactic infusions, in order to improve the compliance of families to such a highly demanding treatment (whose perceived need and knowledge of benefits are often poor), and, in particular, to reduce the need for central venous access devices, reaching full-dose regimens when children may have good peripheral vein accesses."[2]

These approaches are based off of Swedish and Canadian methods, showing that methods can be different in different parts of the world. With tailored doses initiated early, the body can use its peripheral veins rather than central veins to receive factor VIII.

The third idea I would like to discuss is the hemophilia situation in Singapore, just to give an idea of the conditions they face: "Two recombinant factor VIII products are currently marketed in Singapore for haemophiliacs. Their tangible benefits are difficult to disregard, but their cost only serves to aggravate the headaches of all concerned, as we struggle to provide even the least exorbitant of clotting factors to patients. Due credit must, however, go to the industry for attempting to reduce the price difference between the plasma-derived and the recombinant clotting factors. The retort of supporters of plasma-derived clotting factors is that the latter are less likely to induce the generation of inhibitors. Indeed, inhibitor development is the bane of haemophilia treatment, as they nullify the usual replacement products. The issue of which product type is the more immunogenic remains unresolved, and is the subject of intense clinical study by both proponents and opponents of this hypothesis."[3]

"While the holy grail of haemophilia treatment is to correct the genetic defect through gene therapy, this approach remains an unrealized potential."[3]

Certainly without further reading, things seem quite dismal. Yet there is hope!

The fourth idea I would like to discuss is the future of recombinant factor VIII: "Will a way forward be found? Given the tremendous progress in hemophilia over the past 40 years, it is likely that the hemophilia community will indeed find a new development. Perhaps prospective clinical trials will be started to address the question directly. Perhaps recombinant von Willebrand protein will be developed and its addition to recombinant factor VIII will be tested in prospective randomized clinical trials. Perhaps the pegylated liposome factor VIII product currently in phase 3 clinical trial will prove further useful as a carrier molecule for factor VIII, and the risk of inhibitor formation will be as low as the heralded low risk for plasma-derived von Willebrand protein containing factor VIII products. Hopefully, the hemophilia community will participate actively in the clinical trials needed to address these questions. Of the many possibilities it is certain only that the future will be interesting."[5]

"The hemophilia community has achieved a remarkable goal for treatment of severe hemophilia A: normal life expectancy for a previously life threatening disease. Now, the challenges will be to improve further the quality of the life of an individual with severe hemophilia A, and to reduce the burden of current treatment strategies on families and medical resources. Promising new recombinant factor VIII products are in advanced stages of clinical trials, and studies are underway to address how to optimally use current resources to improve quality of life for individuals with severe hemophilia A."[5]

My hypothesis is that, with DNA transplants in the future, hemophilia could be eradicated. With the body retaught through gene therapy to produce its own Factor VIII clotting protein, the dependency on outside synthetic Factor VIII would be reduced and hemophilia would disappear. As we have seen in the last 60 years of hemophilia A treatment evolution, there has been a reduction in other diseases being transmitted through Factor VIII transfusion. Also, the recombinant factor VIII is surely evolving generation by generation. In the future, what we could look forward to is the infusion of genetic code, with errors also being strained out of the process.

There was an article published in January of 2010 (published online on December 29, 2009) indicating positive results in gene therapy test results with mice. "This study suggested that a single administration of an advanced generation LV carrying the human FVIII cDNA resulted in elevation of FVIII level in immune competent rats, and that this gene transfer approach to the skeletal muscle could be an effective tool in treatment of hemophilia A."[7]

The importance of the goals of my studies in research of hemophilia, are to learn what types of treatment are currently available, and what is on the horizon. These goals are important because this disease was once untreatable, and now is currently in a very sensitive stage, in which those that once thought that their lives would be cut short, can now expect to live a normal life span, and only have a better and brighter future waiting ahead for them, thanks to the research being done on their disorder.

Bibliography

1. Peng, Aaron, Puneet, Gaitonde, Kosloski Matthew, Miclea Razvan, Varma Prashant, and Balu-Lyer Sathy. "Effect of route of administration of human recombinant Factor VIII on its immunogenicity in Hemophilia A mice." J Pharm Sci (2009): 4480-4484. Web. 25 Mar 2010. .

2. Antonio, Coppola, Di Capua Mirko, and De Simone Ciro. "Primary prophylaxis in children with haemophilia." Blood Transfusion 6.s2 (2008): s4-s11. Web. 25 Mar 2010. .

3. Ng, Heng Joo and Heng, Lee Lai. "Haemophilia in 21st century Singapore." Ann Acad Med Singapore (2009): 378-2. Web. 25 Mar 2010. .

4. Kempton, Christine L., and Gilbert C. White. "How we treat a hemophilia A patient with factor VIII inhibitor." Blood 113.1 (2009): 11-17. Web. 25 Mar 2010. .

5. Powell, Jerry S. "Recombinant factor VIII in the management of hemophilia A: current use and future promise." Therapeutics and clinical risk management 5. (2009): 391-402. Web. 25 Mar 2010. .

6. "Haemophilia." Wikipedia. Wikimedia Foundation, Inc., 26 March 2010 . Web. 26 Mar 2010. .

7. Jeon, Hyun Jeong, Tae Keun Oh, Oak Hee Kim, and Seung Taik Kim. "Delivery of Factor VIII Gene into Skeletal Muscle Cells Using Lentiviral Vector." Yonsei Medical Journal 51.1 (2010): 52-57. Web. 26 Mar 2010. .